IGF-1, also known as somatomedin C, is a serum polypeptide which mediates the activity of growth hormones and also possesses insulin-like activity. Humbel, R. E. (990) European Journal of Biochemistry. 190, 445-462 "Insulin-like Growth Factors I and II" IGF-1 has known insulin-like potency and stimulation potency of sulphate uptake by cartilage, and it may enhance protein and DNA synthesis in cells. It is therefore useful as a growth promoter and for the treatment of diabetes. IGF-1 may be used in humans to treat growth hormone deficiencies, in farm animals to increase growth rates, increase the relative proportion of muscle or improve food conversion efficiency in humans to suppress the loss of body protein in severe catabolic states such as following burns, infection or other trauma, in humans and animals to improve wound healing and to support the growth of cells in culture. IGF-1 may be used for the treatment of disorders associated with tissue wasting including burns, skeletal trauma, infection, cancer, cystic fibrosis, Duchenne muscular dystrophy, Becker dystrophy, autosomal recessive dystrophy, polymyositis as well as other myopathies and AIDS. IGF-1 may be used for the treatment of protein accumulation deficiencies in mammals. Specific deficiencies are those associated with infant prematurity, growth hormone deficiency, somatomedin deficiency, burns, infection, other trauma, cancer, cystic fibrosis, Duchenne muscular dystrophy, Becker dystrophy, autosomal recessive dystrophy, polymyositis, as well as other myopathies and AIDS. IGF-1 may be used to stimulate erythropoiesis and is therefore useful in humans for treating growth deficiencies and for restricting negative nitrogen balance associated with catabolic conditions. Consequently, it is desirable to have IGF-1 analogs possessing greater than natural activity.
These analogs are of applicable importance for treatment of catabolic states such as diabetes where there is a deficiency in both insulin and IGF-1 activity.
The structure-activity relationship of IGF-1 has been approached from synthetic, semisynthetic, and biosynthetic methods. DiMarchi, et al. reported the importance of C domain to the attainment of full IGF-1 receptor affinity. "Synthesis of a fast acting insulin based on structural homology with insulin-like growth factor I", DiMarchi, R. D., et al. in Peptides: Chemistry and Biology; Proceedings of the Twelfth American Peptide Symposium, Jun. 16-21, 1991 Cambridge Mass., (1992) Smith, J. A. and Rivier, J. E. eds., pp.26-28 ESCOM, Leiden. The two-chain IGF-1 equivalent of insulin was reported to possess nearly equal affinity for the insulin and IGF-1 receptor. Additional two-chain IGF-1 related peptides that possess appreciable substitutions with insulin residues have been prepared. In all instances the potency of these heterodimeric IGF-1 species have displayed reduced affinity for the IGF-1 receptor relative to that of the analogous IGF-1 ligand. Biosynthesis of IGF-1 analogs has been exclusively focused on single-chain peptides. Cascieri, M. A., et i. (1988) Biochemistry 27:3229-3233; Bayne, M. L. et al. (1988) J. Biol. Chem. 249:11004-11008.
We have surprisingly observed that where complete removal of the C domain reduces IGF-1 potency, partial removal of the C domain in split IGF-1 molecules yields superagonists. This observation is in contrast to the insulin receptor where we observe a steady increase in insulin receptor affinity with sequential degradation of he C domain. The divergent performance at these two highly homogolous receptors was totally unexpected. It has provided unique IGF-1 analogs that are superagonists at the IGF-1 receptor and as an additional benefit possess significantly greater insulin potency than the natural